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R.T. Williams: Founding of the Field

The modern field of xenobiotic metabolism grew from the convictions of a Welshman named R. Tecwyn Williams (pictured left) His early experiences elucidating the ring structure of glucuronic acid involved isolation of bornyl glucuronide from the urine of dogs fed borneol. He was able to crystallize this conjugate and use it as a source material for his publication on the pyranoid structure of glucuronic acid in Nature in 1931. This work stimulated his interest in the metabolism of foreign compounds and led to a series of papers on the fate of phenols, terpenes and sulphonamides. Williams became convinced that the biochemistry of foreign compounds was just as important as that of natural body constituents. The discovery of Prontosil by Domagk and the finding that its antibacterial activity was due to metabolic conversion to the sulphonamide spurred great interest in the processes of metabolism and their importance in the fate of drugs and other foreign compounds.

During the late 1930s Williams decided to write a book on the detoxication of foreign compounds but, because of the war, it didn't come to fruition until 1947. The original book was a slim volume summarizing much of the metabolism work that had been done to date. In the 1950s, metabolic studies on a broad range of compounds added considerably to the systemization of the metabolic routes of xenobiotics, culminating in publication of an expanded "Detoxication Mechanisms" in 1959. This book is still a marvel of organization and enlightenment. It provides a systematic approach based on organic chemistry classification.

Williams also expanded on his concepts of the principal biochemical reactions whereby drugs and other foreign compounds are metabolized in the body. Most importantly, he proposed that foreign compounds were metabolized in two distinct phases: one including oxidations, reductions, and hydrolyses and the other comprised of conjugation reactions.

Williams was displeased with the short title of his book since he was aware of many instances where metabolism actually increased toxicity. He stated his feelings clearly in the last paragraph of the Second Edition:

It is clear that, from the point of view of detoxication, phase I reactions cannot be considered as detoxication mechanisms, although in many cases detoxication does occur as a result of these reactions. Phase II reactions on the other hand appear to be largely processes of detoxication but again exceptions occur. It is therefore very difficult to decide to what extent a systematic true detoxication occurs in the body. Detoxication nevertheless occurs, but with an entirely foreign compound it is largely a matter of chance whether it takes place efficiently enough to protect the organism completely from the noxious effects of the foreign compound.